A strong body of evidence implicates cerebrovascular ss-amyloid (cerebral amyloid angiopathy or CAA) as a relatively common independent contributor to cognitive impairment in the elderly, most likely by effects on vessel function. Unlike other common small vessel pathologies, CAA remains both unpreventable and untreatable. This renewal proposal seeks to establish the pathophysiologic mechanisms that lead from vascular amyloid deposition to focal brain injury to neurologic impairment. It builds on the considerable success of the productive initial funding period in establishing a range of novel noninvasive markers for CAA, including increasingly sensitive detection of cerebral microbleeds, surprisingly frequent silent microinfarcts, impaired cerebrovascular reactivity, and detection of vascular amyloid itself by Pittsburgh Compound B. The proposal also takes advantage of the Principal Investigator's expertise in the diagnosis, genetics, clinical course, and pathophysiology of CAA and his group's well-characterized cohort of patients diagnosed with this disorder. Specific Aim 1 examines the cross-sectional association between location and severity of vascular amyloid and the extent of focal structural lesions, brain atrophy, and neurologic dysfunction. This aim tests the hypothesis that cortical amyloid accumulation triggers cerebral microbleeds, microinfarcts, increased diffusivity, and focal brain atrophy, which in turn lead to impaired cognitive performance, gait, and functional skills. Specific Aim 2 tests the specific role in this pathogenic cascade of two candidate vascular mechanisms as potential mediators of CAA-related brain injury: impaired cerebrovascular reactivity and reduced transvascular water exchange. Specific Aim 3 is a prospective, longitudinal analysis aimed at determining the causal relationship between location and severity of vascular abnormalities at baseline and appearance of new structural lesions on follow-up MRI or incident neurologic decline, defined as dementia, loss of functional independence, or death. This proposal brings together a productive multidisciplinary team with recognized expertise in patient-oriented investigation and multimodal neuroimaging. Successful achievement of these aims will establish a strong foundation for anticipated clinical drug trials for CAA, in which candidate agents will be selected by their ability to target key vascular mechanisms and screened for their ability to slow progression of key biomarkers. PUBLIC HEALTH RELEVANCE: We propose a study of how cerebral amyloid angiopathy (or CAA), an age-related degenerative condition of the blood vessels in the brain, causes loss of cognitive skills. Severe CAA occurs in up to 31% of older people and up to 43% of older people with dementia and is both unpreventable and untreatable. We propose to use innovative imaging tools to identify the steps that lead from CAA to brain injury and problems with cognition. These studies will create a strong foundation for starting treatment trials aimed at preventing this major threat to our aging population.